Emerging Role of the Inflammasome and Pyroptosis in Hypertension

Abstract

Inflammasomes are components of the innate immune response that have recently emerged as crucial controllers of tissue homeostasis. In particular, the nucleotide-binding domain, leucine-rich-containing (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is a complex platform involved in the activation of caspase-1 and the maturation of interleukin (IL)-1β and IL-18, which are mainly released via pyroptosis. Pyroptosis is a caspase-1-dependent type of cell death that is mediated by the cleavage of gasdermin D and the subsequent formation of structurally stable pores in the cell membrane. Through these pores formed by gasdermin proteins cytosolic contents are released into the extracellular space and act as damage-associated molecular patterns, which are pro-inflammatory signals. Inflammation is a main contributor to the development of hypertension and it also is known to stimulate fibrosis and end-organ damage. Patients with essential hypertension and animal models of hypertension exhibit elevated levels of circulating IL-1β. Downregulation of the expression of key components of the NLRP3 inflammasome delays the development of hypertension and pharmacological inhibition of this inflammasome leads to reduced blood pressure in animal models and humans. Although the relationship between pyroptosis and hypertension is not well established yet, pyroptosis has been associated with renal and cardiovascular diseases, instances where high blood pressure is a critical risk factor. In this review, we summarize the recent literature addressing the role of pyroptosis and the inflammasome in the development of hypertension and discuss the potential use of approaches targeting this pathway as future anti-hypertensive strategies.

NLRP3 Inflammasome in Vascular Disease: A Recurrent Villain to Combat Pharmacologically

“…Once activated, JNK and p38 induce the activation of transcription factors that are involved in the expression of pro-inflammatory genes, such as ATF2 and AP1 [ 23 ]. Another consequence of NLRP3 activation is the induction of pyroptosis, a pro-inflammatory cell death leading to an increment in the production and release of IL-1β and IL-18, which contributes to the maintenance of a pro-inflammatory environment [ 26 ] and has been demonstrated to contribute to vascular disease [ 27 ].…”

Salt-Sensitivity of Blood Pressure and Insulin Resistance

“…IL-1β and IL-18, the main products of NLRP3 activation, are elevated in plasma and monocytes of hypertensive individuals ( Dörffel et al, 1999 ; Li et al, 2005 ; Rabkin, 2009 ) and associate with renal and vascular dysfunction ( De Miguel et al, 2021 ). Hypertensive patients also have high concentrations of NF-κB, a crucial intracellular trigger of NLRP3 activation, in tissue and inflammatory cells ( De Miguel et al, 2021 ). NF-κB inhibition ameliorates hypertension and prevents hypertension-induced organ damage in mice ( Zambom et al, 2019 ).…”

Molecular Interactions of Arterial Hypertension in Its Target Organs

“…The compounds of the immune system are managed to produce vasoactive molecules, such as Ang II, endothelin-1 or prostaglandins. All of them are known as the hypertensive mediators and TOD mediators [ 22 ]. These data showed that monocytes and macrophages enhance vasoconstriction and sodium retention.…”

“…The knockout of Krüppel-like factor-15 expression, which promotes the Il-11 production, might be another target for decreasing the vascular remodeling in AH [ 30 ]. It is important to note that the accumulation of immune cells within the tissue leads to local production of hypertensive mediators, such as Ang II, and increase the local levels of hypertensive stimuli within the kidneys, vasculature or nervous system [ 22 ]. Lately, extensive evidence demonstrates the role of brain perivascular macrophages (PVMs) in the development of AH.…”